Complement System Dysregulation and Inflammation in the Retinal Pigment Epithelium of a Mouse Model for Stargardt Macular Degeneration

Radu, Roxana A.; Hu, Jane; Yuan, Quan; Welch, Darcy L.; Makshanoff, Jacob; Lloyd, Monte; McMullen, Stephen; Travis, Gabriel H.; Bok, Dean

doi:10.1074/jbc.m110.191866

Cited by 142 publications

(167 citation statements)

References 45 publications

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“…These damaging photodegradative processes and associated bisretinoid loss may also explain the predilection of the macula for disease. In support of this association are results showing that mice burdened with augmented bisretinoid formation monitored as elevated A2E and all-trans-retinal dimer, exhibit accentuated carbonyl-adduct deposition in Bruch's membrane, excessive complement activation, Bruch's membrane thickening due to basal laminar deposits, and accelerated loss of photoreceptor cells compared with WT mice (25)(26)(27)(28)(29)(30). Additionally, albino Abca4 −/− mice exhibit an increased susceptibility to retina light damage (31).…”

Section: What Are Vitamin A-aldehyde Adducts?supporting

confidence: 54%

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Sparrow

2016

Proc. Natl. Acad. Sci. U.S.A.

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Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.age-related macular degeneration | vitamin A-aldehyde adducts | bisretinoids | retinal pigment epithelium | photoreceptor cells Age-related macular degeneration (AMD) is a complex disorder that is predicted to have a growing impact on elderly populations. Although the cause of central vision loss in AMD is the progressive impairment of photoreceptor cells, the disease is generally thought to begin with dysfunctioning of retinal pigment epithelium (RPE) and adverse changes in subjacent Bruch's membrane (1, 2). The early stage of the disease is typically marked by extracellular accumulations (drusen) between RPE and Bruch's membrane. Progression to advanced disease is defined by delineated areas devoid of RPE and photoreceptor cell loss (atrophic AMD) and/or abnormal growth of blood vessels underneath RPE or within the subretinal space (neovascular AMD). AMD Risk FactorsAMD susceptibility is influenced by multiple factors of both genetic and environmental origin. Predisposing genetic factors account for 71% of the variation in disease risk among individuals (3). Currently, 52 independently associated genetic variants at 34 loci are known to account for ∼50% of AMD heritability (4). The genes implicated by these variants belong to multiple systems some of which are associated with the complement pathway, lipid metabolism, and maintenance of extracellular matrix (5, 6). Nevertheless, many individuals carrying risk variants do not develop AMD.Two loci, CFH (complement factor H; 1q31) and ARMS2/HTRA1 (age-related maculopathy susceptibility 2/high-temperature requirement factor A1; 10q26), make the greatest contribution to AMD risk. Variants at the ARMS2/HTRA1 and CFH loci significantly increase risk for progression to both the atrophic and neovascular forms of AMD, although the magnitude of the association of the ARMS2/HTRA1 risk allele is somewhat greater for the neovascular phenotype of late AMD, whereas CFH risk variants favor progression toward geogr...

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Section: What Are Vitamin A-aldehyde Adducts?supporting

confidence: 54%

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Sparrow

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A2E exhibits several mechanisms of cytotoxicity and is implicated in the pathogenesis of STGD1 (26 -32). Interestingly, Abca4 Ϫ/Ϫ mice exhibit dysregulation of the complement system and signs of complement-mediated inflammation in the RPE before the onset of photoreceptor degeneration (25,33). These observations establish a connection between bisretinoid accumulation and complement activation in vivo.…”

mentioning

confidence: 61%

“…Primers sequences and qRT-PCR conditions have been reported previously by our laboratory (33). Data were normalized to 18 S rRNA Ct values for each sample.…”

Section: Cultured Fetal Human Retinal Pigment Epithelial Cells-mentioning

confidence: 99%

“…Wild-type and Abca4 Ϫ/Ϫ OS samples were prepared freshly as a bulk, ensuring that both YY402 and HH402 received the same amount of bisretinoids for each experiment (average of four mouse retinas in 250 l of DMEM per transwell). Qualitative analysis of the mouse OS samples was performed by high-performance liquid chromatography using methods published previously to evaluate the bisretinoid content (33 Transepithelial Resistance Measurements-Fetal hRPE cells were grown on culture wells for 2 months until they reached confluence as a monolayer. Using an epithelial volt Ohm meter (EVOM, World Precision Instruments, New Haven, CT), experimental hRPE transepithelial resistance was measured before and after exposure of the cells to mouse OS and serum.…”

Section: Cultured Fetal Human Retinal Pigment Epithelial Cells-mentioning

confidence: 99%

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Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Radu

Jiang

et al. 2014

Journal of Biological Chemistry

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Background: AMD and STGD1 are blinding diseases with similar clinical presentations but unrelated genetic causes. Results: Bisretinoid-dependent complement reactivity on RPE cells involves the alternative pathway and depends on the CFH haplotype. Conclusion: Inefficient CFH synthesis because of either Y402H and I62V substitutions or bisretinoid accumulation predisposes RPE cells to disease. Significance: These results suggest a common inflammatory etiology for AMD and STGD1.

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“…Retinal inflammation is closely associated with the pathogeneses of human retinal diseases, including retinitis pigmentosa, Stargardt disease, and AMD (43,55). Moreover, infiltrating macrophages are thought to participate in the inflammation associated with retinal degeneration (56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

Maeda

Palczewska

Golczak³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Atrophic age-related and juvenile macular degeneration are especially devastating due to lack of an effective cure. Two retinal cell types, photoreceptor cells and the adjacent retinal pigmented epithelium (RPE), reportedly display the earliest pathological changes. Abca4 −/− Rdh8 −/− mice, which mimic many features of human retinal degeneration, allowed us to determine the sequence of light-induced events leading to retinal degeneration. Using two-photon microscopy with 3D reconstruction methodology, we observed an initial strong retinoid-derived fluorescence and expansion of Abca4 −/− Rdh8 −/− mouse rod cell outer segments accompanied by macrophage infiltration after brief exposure of the retina to bright light. Additionally, light-dependent fluorescent compounds produced in rod outer segments were not transferred to the RPE of mice genetically defective in RPE phagocytosis. Collectively, these findings suggest that for light-induced retinopathies in mice, rod photoreceptors are the primary site of toxic retinoid accumulation and degeneration, followed by secondary changes in the RPE.

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Complement System Dysregulation and Inflammation in the Retinal Pigment Epithelium of a Mouse Model for Stargardt Macular Degeneration

Abstract: Accumulation of vitamin A-derived lipofuscin fluorophores in the retinal pigment epithelium (RPE) is a patho

Cited by 142 publications

References 45 publications

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics

Bisretinoid-mediated Complement Activation on Retinal Pigment Epithelial Cells Is Dependent on Complement Factor H Haplotype

Two-photon microscopy reveals early rod photoreceptor cell damage in light-exposed mutant mice

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